Cancer is one of the leading causes of death in the industrial world. In order to improve patient care, much effort is currently put into finding additional information related to the prognosis, early indications of treatment response, and disease progression. An interesting tool to this end is the use of cancer biomarkers, i.e. substances which are indicative of the presence of cancer in the body. A biomarker may be a molecule secreted by a tumor or a specific response of the body to the presence of cancer. Ideally, such biomarkers can be assayed in non-invasively collected biofluids like urine, blood or serum.
One area of interest is lung cancer, which is the most common and the most deadly cancer disease worldwide. Lung cancer kills more people than colon, breast, and prostate combined (WHO statistics). Approximately 80-85% of lung cancer patients are of non-small cell histology (NSCLC). Small cell lung cancer (SCLC) comprises about 15-20% of all lung cancer cases. The majority of the patients present with advanced and inoperable disease. Resection remains essentially as the only curative treatment for early stage NSCLC. During the last decade a panel of tumor markers have been investigated for their value in lung cancer. The most common biomarkers found to be of clinical significance in lung cancer were CEA, CYFRA, TPA, TPS and NSE. However, the lack of sensitivity and specificity limits the use of cancer biomarkers for screening and early diagnosis of lung cancer. For the prognostic evaluation and monitoring the course of the disease, the cancer biomarkers appear to be more effective.
All eucaryotic cells have cytoplasmic cytoskeletal structures known as intermediate filaments. The cytoskeletal network is responsible for the mechanical integrity of the cell and it is critical during cellular processes like cell division, motility and cell to cell contacts. At present more than 20 different cytokeratins have been identified, of which cytokeratin 8, 18 and 19 are the most abundant in simple epithelial cells. The cytokeratins are epithelial cell specific and the cytokeratin pattern is usually preserved during the transformation of normal cells into malignant cells.
A solid phase two-site immunoradiometric assay (IRMA) that measures defined epitopes on cytokeratins 8, 18 and 19 is commercially available (IDL Biotech, Bromma Sweden) under the trade mark MonoTotal®. The catcher antibodies, the monoclonal antibodies 6D7 (CK8), 3F3 (CK18) and IDLC4 (CK19), are coated on plastic beads. Polyclonal 125I-labeled antibodies are used as tracer in the assay. The radioactivity is measured in a gamma counter and is proportional to the concentration of cytokeratin antigen fragments. MonoTotal is a quantitative test designed for patient serum testing. MonoTotal is valuable for diagnosis, prognosis, as a prognostic marker and for monitoring treatment of patients. By following the patient with repeated MonoTotal measurements, the physician can obtain critical information about tumor cell activity. A changed MonoTotal marker level indicates changes in tumor cell activity, and elevated levels pointing to the presence of a tumor. This information is considered particularly important during patient management and follow-up, where a blood sample may contribute to the monitoring of therapy and early detection of tumor recurrence. Approximately 15% of the lung cancer patients are diagnosed when the disease is still restricted to the lungs and early detection is critical to increase the chances of survival. By using MonoTotal the physician can get an indication of the course of the disease, measured in terms of tumor cell activity instead of the more conventional tumor load measurements. MonoTotal can provide the physician with a reliable aid for diagnosis, in establishing prognosis, in treatment monitoring and in patient follow-up.
According to published studies, MonoTotal has been shown to have strong association with clinical response in patients. MonoTotal demonstrates much higher sensitivity compared to Cyfra in lung cancer patients. The overall sensitivity of MonoTotal in the diagnosis of lung cancer, independent of histotype, is about 70-75% at 95% specificity. The sensitivity of non-small cell lung cancer (NSCLC) is higher. MonoTotal correlates well with tumor cell activity and the extent of the disease. Furthermore, MonoTotal predicts disease progression (disease free interval and overall survival) and is an early indicator of relapse during follow up in NSCLC. Changes in MonoTotal often precede detection of relapse by conventional image methods. Response to treatment can be detected within few days since the half-life of cytokeratin proteins in serum are less than one day. MonoTotal is a more sensitive tumor marker for NSCLC than the other cytokeratin markers currently used in routine clinical practice.
Another area of interest is bladder cancer, which is a common cancer in men and women worldwide. More than 70 percent of cases are non-muscle invasive bladder cancers, but many patients progress to muscle invasive bladder cancer or metastatic disease. To improve the prognosis ofbladder cancer, employing effective methods for early detection and regular follow-up is vital for the patient.
Non-invasive bladder cancer tests have many potential applications, such as helping to diagnose recurrence, reducing the need for invasive testing, and detecting whether patients fall into a high-risk category. UBC® immunoassays (IDL Biotech) are one type of non-invasive test.
However, despite the methods and assays currently on the market, there is still a need for improved diagnostics tools to capture critical clinical data from patients, avoiding disadvantages related to the use of polyclonal antibodies while enabling efficient detection of early signs of disease and a quick measurement of disease status in patients, for example through serum or urine analysis. It is crucial in this area that products and processes meet high quality standards, and are developed, manufactured, and supplied to the market according to standardized procedures.